5-alkenyl and 5-alkynyl indole compounds

Described herein are compounds selective for 5-HT.sub.1D -like receptors, which have the general formula: ##STR1## wherein: R.sup.1 is selected from H, aryl and aryl substituted with 1, 2 or 3 substituents independently selected from loweralkyl, loweralkoxy, loweralkylcarbonyl, loweralkyl-S--, loweralkyl-S(O)--, loweralkyl-SO.sub.2 -, S.dbd.C.dbd.N--, O.dbd.C.dbd.N--, halo, loweralkoxycarbonyl, nitro, amino, loweralkyl-NH--, (loweralkyl).sub.2 --N--, loweralkyl-SO.sub.2 -loweralkyl-;A is a double or triple bond;R.sup.2 is selected from a group of Formula II, III, IV and V: ##STR2## R.sup.3 is selected from H and loweralkyl; R.sup.4 is selected from H and loweralkyl;One of R.sup.5 and R.sup.6 is H and the other is independently selected from H, loweralkoxy, loweralkyl and hydroxy; andR.sup.7 and R.sup.8 are independently selected from H and loweralkyl or R.sup.7 and R.sup.8, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 6-membered ring;or a salt, solvate or hydrate thereof.Also described is the use of these compounds as pharmaceuticals to treat indications where stimulation of the 5-HT.sub.1D -like receptor is implicated, such as migraine.

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Claims

1. A compound according to Formula I: ##STR34## wherein: R.sup.1 is selected from the group consisting of H, aryl and aryl substituted with 1, 2 or 3 substituents independently selected from the group consisting of loweralkyl, loweralkoxy, loweralkylcarbonyl, loweralkyl-S--, loweralkyl-S(O)--, loweralkyl-SO.sub.2 -,S.dbd.C.dbd.N--, O.dbd.C.dbd.N--, halo, loweralkoxycarbonyl, nitro, amino, loweralkyl-NH--, (loweralkyl).sub.2 -N--, and loweralkyl-SO.sub.2 -loweralkyl-;

A is --CH.dbd.CH-- or --C.ident.C-- (a vinyl or alkynyl group)
R.sup.2 is selected from the group consisting of Formula II, III, IV and V: ##STR35## R.sup.3 is H or loweralkyl; R.sup.4 is H or loweralkyl;
one of R.sup.5 and R.sup.6 is H and the other is independently selected from the group consisting of H, loweralkoxy, loweralkyl and hydroxy; and
R.sup.7 and R.sup.8 are independently selected from the group consisting of H and loweralkyl or R.sup.7 and R.sup.8, form an alkylene bridge which, together with the nitrogen atom to which they are attached, creates an unsubstituted or substituted 3- to 6-membered ring;

2. A compound according to claim 1, wherein R.sup.1 is H.

3. A compound according to claim 1, wherein R.sup.1 is selected from the group consisting of phenyl, thienyl, and imidazolo, wherein R.sup.1 is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of loweralkyl, loweralkoxy, loweralkylcarbonyl, loweralkyl-S--, loweralkyl-SO.sub.2, S.dbd.C.dbd.N--, halo, loweralkoxycarbonyl, nitro, loweralkyl-SO.sub.2 -loweralkyl- and pyrrolo.

5. A compound according to claim 2, wherein A is vinyl.

6. A compound according to claim 1, wherein R.sup.2 is a group of Formula II.

7. A compound according to claim 6, wherein R.sup.3 is methyl.

8. A compound according to claim 1, wherein R.sup.2 is a group of Formula III.

9. A compound according to claim 8, wherein R.sup.4 is methyl.

10. A compound according to claim 1, wherein R.sup.2 is a group of Formula IV.

11. A compound according to claim 10, wherein R.sup.5 and R.sup.6 are both H.

12. A compound according to claim 11, wherein R.sup.7 and R.sup.8 are both methyl.

13. A compound according to claim 10, wherein R.sup.7 and R.sup.8, together with the nitrogen atom to which they are attached, form a pyrrolidine ring.

14. A compound according to claim 1, wherein R.sup.2 is a group of Formula V.

15. A compound according to claim 14, wherein R.sup.5 and R.sup.6 are both H.

20. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in an amount effective to stimulate a 5-HT.sub.1D -like receptor, a compound as defined in claim 1.

22. A pharmaceutical composition according to claim 21, wherein said compound is one in which R.sup.1 is H.

23. A pharmaceutical composition according to claim 22, wherein said compound is one in which A is vinyl.

24. A pharmaceutical composition according to claim 20, wherein said compound is one in which R.sup.2 is a group of Formula III and R.sup.4 is methyl.

25. A pharmaceutical composition according to claim 20, wherein said compound is one in which R.sup.2 is selected from the group consisting of Formula IV and Formula V.

26. A pharmaceutical composition according to claim 25, wherein said compound is one in which R.sup.5 and R.sup.6 are both H.

27. A pharmaceutical composition according to claim 26, wherein said compound is one in which R.sup.7 and R.sup.8 are both methyl.

28. A pharmaceutical composition according to claim 26, wherein said compound is one in which R.sup.7 and R.sup.8, together with the nitrogen atom to which they are attached, form a pyrrolidine ring.

29. A method for treating a patient having a medical condition for which a 5-HT.sub.1D -like receptor agonist is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in claim 20.

30. A method for treating a patient according to claim 29, wherein the medical condition is migraine.

Referenced Cited
U.S. Patent Documents
4870085 September 26, 1989 Glaser et al.
5348968 September 20, 1994 Lavielle et al.
5496957 March 5, 1996 Glennon
5504101 April 2, 1996 Glennon
Foreign Patent Documents
02037351B August 1990 JPX
WO 9402477 February 1994 WOX
WO 9424127 October 1994 WOX
WO 9617842 June 1996 WOX
Other references
  • Glen, et al. Journal of Medicinal Chemistry, 1995, 38:3566-3580. "Computer-Aided Design and Synthesis of 5-Substituted Tryptamines and Their Pharmacology at the 5-HT1D Receptor: Discovery of Compounds with Potential Anti-Migraine Properties".
Patent History
Patent number: 5856510
Type: Grant
Filed: Dec 16, 1996
Date of Patent: Jan 5, 1999
Assignee: Allelix Biopharmaceuticals Inc. (Mississauga)
Inventors: Oingchang Meng (Georgetown), Abdelmalik Slassi (Mississauga), Louise Edwards (Mississauga), Sumanas Rakhit (Misssissauga)
Primary Examiner: Floyd D. Higel
Law Firm: Nikaido, Marmelstein, Murray & Oram LLP
Application Number: 8/767,322